Salt-sensitivity (SS) of blood pressure (BP) is a quantitative trait in which an increase in sodium (Na+) load engenders an increase in BP. SS predicts increased cardiovascular events and mortality, irrespective of baseline BP. SS is present in 50% of the hypertensive and 26% of the normotensive population, posing a major public health problem. The molecular mechanisms underlying salt- sensitivity are poorly understood. The overall hypothesis for this project is that exposure to Na+ in human subjects with high SLC4A5 risk alleles combined with GRK4?R65L alleles increases the activities of Na+ transporters in the kidney proximal tubule, leading to increased Na+ transport and SS. To test this hypothesis, we will phenotype subjects with and without high risk SLC4A5 and GRK4?R65L alleles for Na+ metabolism during acute Na+ loading. The Specific Aims of this project are: (1) To test the hypothesis that human subjects with combined high risk SLC4A5 and GRK4R65L alleles have impaired renal Na+ excretion due to increased RPT Na+ reabsorption compared to subjects with only one allele or without these alleles and (2) To test the hypothesis that subjects with combined high risk SLC4A5 and GRK4R65L alleles during high Na+ intake have reduced natriuretic responsiveness to D1R agonist stimulation and increased natriuretic responsiveness to RAS blockade compared to those with only one allele or without these alleles. These studies will clarify the physiological and pathophysiological roles of SLC4A5/NBCe2 and GRK4?R65L for the first time in humans.